Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model. Issue 11 (1st June 2015)

• Record Type: Journal Article
• Authors: Maeda, Dean Y.; Peck, Angela M.; Schuler, Aaron D.; Quinn, Mark T.; Kirpotina, Liliya N.; Wicomb, Winston N.; Auten, Richard L.; Gundla, Rambabu; Zebala, John A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 11(2015)
• Page Start: 2280
• Page End: 2284
• Publication Date: 2015-06-01
• Subjects: CXCR2 -- Antagonist -- Thionicotinamide -- COPD -- Asthma; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)- N -(4-fluoro-phenyl)-nicotinamide6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.